Purification of olmesartan medoxomil

ABSTRACT

The present invention provides a process for purifying olmesartan medoxomil. Also provided is pure olmesartan medoxomil.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.11/217,352, filed Sep. 2, 2005, which claims the benefit of U.S.provisional application Nos. 60/606,437, filed Sep. 2, 2004, and60/638,736, filed Dec. 22, 2004, hereby incorporated by reference.

FIELD OF INVENTION

The present invention relates to processes for purifying olmesartanmedoxomil.

BACKGROUND OF THE INVENTION

The chemical name for olmesartan medoxomil is4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylicacid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (Merck Index 13thed.).

The chemical structure of olmesartan medoxomil is:

The empirical formula is C₂₉H₃₀N₆O₆.

The molecular weight is 558.58.

Olmesartan medoxomil is a prodrug that is hydrolyzed during absorption,and it is a selective AT₁ subtype angiotensin II receptor antagonist.Olmesartan medoxomil is disclosed by U.S. Pat. No. 5,616,599 toYanagisawa et al. It is marketed as BENICAR® in film-coated tablets of 5mg, 20 mg, and 40 mg for treatment of hypertension in a human.

The synthesis of olmesartan medoxomil (OLM-Mod) per se is illustrated asfollows (see also Annul. Rep. Sankyo Res. Lab 2003, 55, 1-91):

The prior art synthetic methods focus on the coupling between thesubstituted imidazole and the substituted biphenyl methylene bromide.Additional synthetic methods for these olmesartan medoxomilintermediates are described by: JP 11302260, JP 11292851, JP 07053489,JP 06298683, U.S. Pat. No. 5,621,134, EP 838458, DE 19757995, U.S. Pat.No. 6,111,114, and U.S. Pat. No. 6,214,999.

Step (vi) (the deprotection step) of the prior art synthesis isillustrated as follows:

Example 61(b) of the '599 patent discloses a process for preparing crudeolmesartan medoxomil from a mixture of trityl olmesartan medoxomil (MTT)and aqueous acetic acid. Col. 176, lines 24-37. Triphenyl carbinol (TPC)is removed, and olmesartan medoxomil is isolated by evaporation.

Because of the acidic conditions and the presence of water, the impurityOLM-acid is also formed during the reaction by hydrolysis of the esterbond. The chemical structure of OLM-acid is:

The empirical formula of OLM-acid is C₂₄H₂₆N₆O₃, and its molecularweight is 446.50. The prior art process yields crude olmesartanmedoxomil containing 2.2% OLM-acid per area percent HPLC. The '599patent also discloses that the compounds can be further purified byconventional means including recrystallization. Col. 64, lines 43-45.BENICAR® contains 0.3% OLM-acid per area percent HPLC.

There is a need for processes that minimize the hydrolysis of the esterbond in olmesartan medoxomil and thus provide a purer product. Further,from an industrial and practical viewpoint, it would be desirable toavoid the need for chromatographic purification steps. The presentinvention provides improved processes for purifying olmesartan medoxomilas well as olmesartan medoxomil with low levels of OLM-acid.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a typical chromatogram for a purified olmesartanmedoxomil sample.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a process for purifyingolmesartan medoxomil including the steps of: providing a solution ofolmesartan medoxomil in a C₃₋₆ ketone, preferably acetone; adding waterto the solution; and recovering purified olmesartan medoxomil. Theprocess can further include the step of heating the solution. Theprocess can further include the step of cooling the solution afteradding water to precipitate purified olmesartan medoxomil.

In another aspect, the present invention provides a process forpreparing olmesartan medoxomil including the steps of: contacting tritylolmesartan medoxomil with an acid in a water miscible organic solvent,with or without water, preferably acetone and water, to obtain a firstsolution of olmesartan medoxomil and a precipitate of triphenylcarbinol; separating the precipitate of triphenyl carbinol from thefirst solution; contacting the first solution with a base to obtain aprecipitate of olmesartan medoxomil; recovering the precipitate ofolmesartan medoxomil; dissolving the precipitate of olmesartan medoxomilin a C₃₋₆ ketone, preferably acetone, to form a second solution; addingwater to the second solution; and recovering the purified olmesartanmedoxomil.

In another aspect, the present invention provides olmesartan medoxomilcontaining less than about 0.3% OLM-acid, more preferably less thanabout 0.05%, and most preferably less than about 0.03%. The presentinvention also provides pharmaceutical compositions containing sucholmesartan medoxomil.

In another aspect, the present invention provides olmesartan medoxomilcontaining less than about 0.15% area by HPLC OLM-acid, more preferablyless than about 0.13% area by HPLC OLM-acid, and most preferably lessthan about 0.12% area by HPLC.

In another aspect, the invention provides a pharmaceutical compositioncomprising olmesartan medoxomil containing less than about 0.15% area byHPLC OLM-acid and at least one pharmaceutically acceptable excipient.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides a process forpurifying olmesartan medoxomil including the steps of: providing asolution of olmesartan medoxomil in a C₃₋₆ ketone; adding water to thesolution; and recovering purified olmesartan medoxomil.

Preferably, the C₃₋₆ ketone is acetone, methyl ethyl ketone, diethylketone, or t-butyl methyl ketone. Most preferably, the C₃₋₆ ketone isacetone.

For providing a solution of olmesartan medoxomil in the C₃₋₆ ketone, apreferable amount of the ketone is at least about 7 volumes ketone toabout 1 gram of solid olmesartan medoxomil, more preferably at leastabout 10 volumes ketone to about 1 gram of solid olmesartan medoxomil.The ketone can contain water, such as about 4% to about 14% water byvolume, preferably about 4% water by volume.

The process can further include the step of heating the solution ofolmesartan medoxomil in the C₃₋₆ ketone. In this embodiment, thesolution of olmesartan medoxomil in the C₃₋₆ ketone is preferably heatedto about 30° C. to about reflux temperature, more preferably about 40°C. to about reflux temperature.

Water is added to precipitate the purified olmesartan medoxomil. Theamount of water added is preferably about 0.5 to about 2 volumes waterto about 1 volume of the C₃₋₆ ketone, more preferably at least about 1:1by volume.

After adding the water, the process can further include a step ofcooling the solution to induce precipitation. The solution can be cooledto a temperature below about 30° C., more preferably to about roomtemperature. As used herein, the term “room temperature” refers to atemperature of about 20° C. to about 30° C., preferably about 20° C. toabout 25° C.

Recovering the purified olmesartan medoxomil can be performed by anymeans known in the art, such as filtration or centrifugation. Theprocess can further include the step of drying the precipitated purifiedolmesartan medoxomil. Drying may be carried out, for example, by heatingto a temperature of about 30° C. to about 60° C. The pressure can bereduced to accelerate the drying process, for example, to below oneatmosphere, more preferably to below about 100 mm Hg.

In another embodiment, the present invention provides a process forpreparing olmesartan medoxomil including the steps of: contacting tritylolmesartan medoxomil with an acid in a water miscible organic solvent toobtain a first solution of olmesartan medoxomil and a precipitate oftriphenyl carbinol; separating the precipitate of triphenyl carbinolfrom the first solution; contacting the first solution with a base toobtain a precipitate of olmesartan medoxomil; recovering the precipitateof olmesartan medoxomil; dissolving the precipitate of olmesartanmedoxomil in a C₃₋₆ ketone to form a second solution; adding water tothe second solution; and recovering the purified olmesartan medoxomil.

Preferred water miscible organic solvents include, but are not limitedto, acetone, acetonitrile, and t-butanol. Acetone is especiallypreferred. Preferably, the trityl olmesartan medoxomil is contacted witha mixture of a water miscible organic solvent and water. Mostpreferably, the trityl olmesartan medoxomil is contacted with a mixtureof acetone and water. Preferably, the ratio of water to the watermiscible organic solvent, e.g., acetone, is preferably about 1:3 toabout 3:1 by volume.

The acid that is contacted with the first solution removes the triphenylcarbinol to form an acid salt of olmesartan medoxomil. Preferably, theacid is a strong acid having a pH of about 0 to about 4. Suitable acidsinclude, but are not limited to, organic acids such as formic acid,acetic acid, benzoic acid, and oxalic acid; oxoacids such as perchloricacid, chloric acid, chlorous acid, hypochlorous acid, sulfuric acid,sulfurous acid, p-toluene sulfonic acid, nitric acid, nitrous acid,phosphoric acid, and carbonic acid; and binary acids such ashydrofluoric acid, hydrochloric acid, hydrobromic acid, hydrocyanicacid, and hydrosulfuric acid. Hydrochloric acid, p-toluene sulfonicacid, and especially sulfuric acid are preferred. Preferably, the amountof acid is about 2 to about 8 equivalents, more preferably about 3 toabout 4 equivalents, and most preferably about 3 equivalents.

When contacting the trityl olmesartan medoxomil with the acid, thetemperature is preferably about 10° C. to about 60° C., more preferablyabout 40° C. In a preferred embodiment, the combination of tritylolmesartan medoxomil, the water miscible organic solvent, and the acidis maintained for about 3 to about 15 hours. Preferably, the combinationis maintained for about 4 to about 6 hours, most preferably for about 4hours.

In a preferred embodiment, prior to separating the triphenyl carbinol,water is added to avoid the formation of undesired by-products.Preferably, the amount of added water is about 2 volumes per gram oftrityl olmesartan medoxomil. Precipitation can be perceived visually asa clouding of the solution or formation of distinct particles of theprecipitate suspended in the solution or collected at the bottom thevessel containing the solution.

Separating the triphenyl carbinol from the solution can be performed byany means known in the art, such as filtration or centrifugation.

After separating the triphenyl carbinol, the olmesartan medoxomilsolution is contacted with a base. Suitable bases include, but are notlimited to, alkali and alkaline earth metal hydroxides, carbonates, andhydrogen carbonate salts. Specific exemplary bases include, but are notlimited to, sodium hydroxide, potassium hydroxide, calcium hydroxide,magnesium hydroxide, sodium carbonate, potassium carbonate, sodiumbicarbonate, potassium bicarbonate, and calcium carbonate. Potassiumcarbonate and especially sodium bicarbonate are preferred. Preferably,the equivalents of base used is about equal to the equivalents of acidused, that is, the amount of base used is preferably about 0.8 to 1.5equivalents compared to the amount of acid used. The base preferablyincreases the pH of the solution, but the solution need not reach abasic pH. After contacting the solution with the base, the solution ispreferably maintained at a temperature of about 2° C. to about 25° C.,preferably at about room temperature. As used herein, the term “roomtemperature” refers to a temperature of about 20° C. to 30° C.,preferably 20° C. to 25° C. The solution is maintained until olmesartanmedoxomil is precipitated.

The precipitate, i.e., the crude olmesartan medoxomil, can then berecovered by any means known in the art, such as filtration orcentrifugation. Olmesartan medoxomil is recovered in its free base form,i.e., the nitrogen on the tetrazole is free.

The reaction progress can be detected by any method known in the art,such as, for example, HPLC, GC, TLC, NMR, and mass spectroscopy.

The processes of the present invention yield olmesartan medoxomil havinglow levels of OLM-acid. All percentages of impurities described hereinare provided as area percentage HPLC at 220 nm. Crude olmesartanmedoxomil prepared according to U.S. Pat. No. 5,616,599 contains 2.2%OLM-acid. In contrast, crude olmesartan medoxomil prepared according tothe present invention contains less than about 1% OLM-acid, e.g., onlyabout 0.89% OLM-acid.

With respect to a purified product, BENICAR® contains 0.3% OLM-acid.Thus, the prior art process reduces the OLM-acid from 2.2% in the crudeolmesartan medoxomil to 0.3%. However, when such crude olmesartanmedoxomil is purified according to the process of the present invention,the amount of OLM-acid is reduced to 0.26%. The amount of OLM-acid canbe further reduced by utilizing crude olmesartan medoxomil preparedaccording to the present invention. When crude olmesartan medoxomilcontains less than about 1% OLM-acid, the purification process of thepresent invention can reduce the OLM-acid level to less than about 0.3%.

The present invention further provides olmesartan medoxomil having lessthan about 0.3% OLM-acid, more preferably less than about 0.05%, andmost preferably less than about 0.03%. The present invention alsoprovides pharmaceutical compositions containing such olmesartanmedoxomil.

The present invention also provides olmesartan medoxomil having lessthan about 0.15% area by HPLC OLM-acid, more preferably less than about0.13% area by HPLC OLM-acid, and most preferably less than about 0.12%area by HPLC. Additionally, the present invention providespharmaceutical compositions containing such olmesartan medoxomil.

Pharmaceutical compositions containing the olmesartan medoxomil asdescribed above can be prepared as medicaments to be administeredorally, parenterally, rectally, transdermally, bucally, or nasally.Suitable forms for oral administration include solid forms such astablets, powders, granulates, capsules, suppositories, sachets, troches,and lozenges, as well as liquid forms such as syrups, suspensions, andelixirs. Suitable forms of parenteral administration include an aqueousor non-aqueous solution or emulsion, while for rectal administrationsuitable forms for administration include suppositories with hydrophilicor hydrophobic vehicle. For topical administration the inventionprovides suitable transdermal delivery systems known in the art, and fornasal delivery there are provided suitable aerosol delivery systemsknown in the art.

In addition to the active ingredient(s), the compositions of the presentinvention can contain one or more excipients or adjuvants. An excipientis an inert ingredient added to a pharmaceutical composition to diluteit or to give it form or consistency. An adjuvant assists the action ofan active ingredient. Selection of excipients and adjuvants and theamounts to use can be readily determined by the formulation scientistbased upon experience and consideration of standard procedures andreference works in the field.

Diluents increase the bulk of a solid pharmaceutical composition, andcan make a pharmaceutical dosage form containing the composition easierfor the patient and care giver to handle. Diluents for solidcompositions include, for example, microcrystalline cellulose (e.g.Avicel®), microfine cellulose, lactose, starch, pregelatinized starch,calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose,dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g. Eudragit®), potassium chloride, powderedcellulose, sodium chloride, sorbitol, and talc.

Solid pharmaceutical compositions that are compacted into a dosage form,such as a tablet, can include excipients whose functions include helpingto bind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions includeacacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulosesodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenatedvegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g.Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquidglucose, magnesium aluminum silicate, maltodextrin, methylcellulose,polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinizedstarch, sodium alginate, and starch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach can be increased by the addition of a disintegrantto the composition. Disintegrants include alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g.Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellosesodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum,magnesium aluminum silicate, methyl cellulose, microcrystallinecellulose, polacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, sodium starch glycolate (e.g. Explotab®), andstarch.

Glidants can be added to improve the flowability of a non-compactedsolid composition and to improve the accuracy of dosing. Excipients thatcan function as glidants include colloidal silicon dioxide, magnesiumtrisilicate, powdered cellulose, starch, talc, and tribasic calciumphosphate.

When a dosage form such as a tablet is made by the compaction of apowdered composition, the composition is subjected to pressure, e.g.,from a punch and dye. Some excipients and active ingredients have atendency to adhere to the surfaces of the punch and dye, which can causethe product to have pitting and other surface irregularities. Alubricant can be added to the composition to reduce adhesion and easethe release of the product from the dye. Lubricants include magnesiumstearate, calcium stearate, glyceryl monostearate, glycerylpalmitostearate, hydrogenated castor oil, hydrogenated vegetable oil,mineral oil, polyethylene glycol, sodium benzoate, sodium laurylsulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that can be included in the composition ofthe present invention include maltol, vanillin, ethyl vanillin, menthol,citric acid, fumaric acid, ethyl maltol, and tartaric acid.

Solid and liquid compositions can also be colored using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions of the present invention, theactive ingredient and any other solid excipients are suspended in aliquid carrier such as water, vegetable oil, alcohol, polyethyleneglycol, propylene glycol, or glycerin.

Liquid pharmaceutical compositions can contain emulsifying agents touniformly disperse the active ingredient(s) and/or insolubleexcipient(s) throughout the composition. Emulsifying agents that can beuseful in liquid compositions of the present invention include, forexample, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth,chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, andcetyl alcohol.

Liquid pharmaceutical compositions of the present invention can alsocontain a viscosity enhancing agent to improve the mouth-feel of theproduct and/or coat the lining of the gastrointestinal tract. Suchagents include acacia, alginic acid bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,polyvinyl alcohol, povidone, propylene carbonate, propylene glycolalginate, sodium alginate, sodium starch glycolate, starch tragacanth,and xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin,sucrose, aspartame, fructose, mannitol, and invert sugar can be added toimprove the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxy toluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid can be added at levels safe for ingestion to improvestorage stability.

According to the present invention, a liquid composition can alsocontain a buffer such as gluconic acid, lactic acid, citric acid oracetic acid, sodium gluconate, sodium lactate, sodium citrate or sodiumacetate.

The dosage form of the present invention can be a capsule containing thecomposition, preferably a powdered or granulated solid composition ofthe invention, within either a hard or soft shell. The shell can be madefrom gelatin and optionally contain a plasticizer such as glycerin andsorbitol, and an opacifying agent or colorant.

Although the most suitable administration in any given case will dependon the nature and severity of the condition being treated, the mostpreferred route of the present invention is oral. The dosages can beconveniently presented in unit dosage form and prepared by any of themethods well-known in the pharmaceutical arts.

A composition for tableting or capsule filling can be prepared by wetgranulation. In wet granulation, some or all of the active ingredientsand excipients in powder form are blended and then further mixed in thepresence of a liquid, typically water, that causes the powders to clumpinto granules. The granulate is screened and/or milled, dried and thenscreened and/or milled to the desired particle size. The granulate canthen be tabletted, or other excipients can be added prior to tableting,such as a glidant and/or a lubricant.

A tableting composition can be prepared conventionally by dry blending.For example, the blended composition of the actives and excipients canbe compacted into a slug or a sheet and then comminuted into compactedgranules. The compacted granules can subsequently be compressed into atablet.

As an alternative to dry granulation, a blended composition can becompressed directly into a compacted dosage form using directcompression techniques. Direct compression produces a more uniformtablet without granules. Excipients that are particularly well suitedfor direct compression tableting include microcrystalline cellulose,spray dried lactose, dicalcium phosphate dihydrate, and colloidalsilica.

A capsule filling of the present invention can comprise any of theaforementioned blends and granulates that were described with referenceto tableting, however, they are not subjected to a final tableting step.

EXAMPLES Example 1 Preparation of Omesartan Medoxomil

A 250 round bottom flask was charged with MTT (10 g), acetone/water (2/2vol.), and 3 eq of H₂SO₄. The combination was stirred at roomtemperature for about 4-6 hrs. Triphenyl carbinol (TPC) was precipitatedby adding water and filtered out. NaHCO₃ was added to the filtrate, andthe mixture was cooled to 5° C. and stirred for 1 hr. Crude olmesartanmedoxomil was obtained as white crystals (90% yield, OLM-acid: 0.89%area by HPLC).

Example 2 Purification (Crystallization) of Olmesartan Medoxomil

A 1 L flask was charged with acetone. Crude olmesartan medoxomil wasadded, and the mixture was heated to reflux for 1 hr and concentrated to10 volumes. The solution was cooled to room temperature, and water (10vol) was added. The mixture was stirred for 1 hr at room temperature,and the precipitate was filtered and dried at 45° C. under 10 mm Hg(yield 87%). The OLM-acid content was 0.04%, as determined by HPLC.

Example 3 Purification (Crystallization) of Olmesartan Medoxomil

A 1 L flask was charged with acetone containing 4% water by volume.Crude olmesartan medoxomil (10 g) was added, and the mixture was heatedto reflux for 1 hr. The solution was cooled to room temperature, andwater (10 vol) was added. The mixture was stirred for 1 hr, and theprecipitate was filtered and dried at 45° C. under 10 mm Hg (yield 90%).The OLM-acid content was 0.04%, as determined by HPLC.

Example 4 Purification (Crystallization) of Olmesartan Medoxomil

A 1 L flask was charged with acetone containing 4% water by volume.Crude olmesartan medoxomil (10 g) was added, and the mixture was heatedto reflux for 1 hr. The solution was cooled to room temperature, andwater (10 vol) was added. The mixture was stirred for 1 hr at 2° C., andthe precipitate was filtered. The solid white powder was dried at 45° C.under 10 mm Hg (yield 95%). The OLM-acid content was 0.07%, asdetermined by HPLC.

Example 5 Purification (Crystallization) of Olmesartan Medoxomil

A slurry of olmesartan medoxomil in acetone (7.5 vol) was heated toreflux for 1.5 hr. The mixture was cooled to room temperature, and water(10 vol) was added. The mixture was stirred for 1 hr at roomtemperature, and the precipitate was filtered and dried at 45° C. under10 mm Hg (yield 91%). The OLM-acid content was 0.06%, as determined byHPLC.

Example 6 Purification (Crystallization) of Olmesartan Medoxomil

A reactor was charged with 50 g of crude olmesartan medoxomil on a drybasis (containing 0.42% OLM-acid), 500 mL (10 vol) acetone, and 20 mL(0.4 vol) water. The mixture was stirred at reflux for 10 minutes untilthe crude olmesartan medoxomil dissolved. The mixture was then cooled to40° C., removed from the reactor, and filtered. The filtrate was thenreturned to reactor at maintained at 40° C. 375 mL (7.5 vol) water wasadded dropwise to the reactor over a period of 40 minutes, causingprecipitation to occur. The reactor content was then cooled to 10° C.over a period of 30 minutes. 125 mL (2.5 vol) of water was then addedand the reactor content was cooled to 0° C. and stirred for 30 minutes.The precipitated solids were filtered, washed with 100 mL (2 vol) ofwater, and dried at 50° C. under reduced pressure to give crystallineolmesartan medoxomil (93% yield). The OLM-acid content was 0.12%, asdetermined by HPLC.

Example 7 Purification (Crystallization) of Olmesartan Medoxomil

A reactor was charged with 50 g of crude olmesartan medoxomil on a drybasis (containing 0.56% OLM-acid), 500 mL (10 vol) acetone, and 20 mL(0.4 vol) water. The mixture was stirred at reflux for 20 minutes untilthe crude olmesartan medoxomil dissolved. The mixture was then cooled to40° C., removed from the reactor, and filtered. The filtrate was thenreturned to reactor at maintained at 40° C. 375 mL (7.5 vol) water wasadded dropwise to the reactor over a period of 35 minutes, causingprecipitation to occur. The reactor content was then cooled to 10° C.over a period of 3 hours. 125 mL (2.5 vol) of water was then added andthe reactor content was cooled to 0° C. and stirred for 3 hours. Theprecipitated solids were filtered, washed with 100 mL (2 vol) of water,and dried at 50° C. under reduced pressure to give crystallineolmesartan medoxomil (92% yield). The OLM-acid content was 0.13%, asdetermined by HPLC.

Example 8 Purification (Crystallization) of Olmesartan Medoxomil

A reactor was charged with 50 g of crude olmesartan medoxomil on a drybasis (containing 0.56% OLM-acid), 500 mL (10 vol) acetone, and 20 mL(0.4 vol) water. The mixture was stirred at reflux for 10 minutes untilthe crude olmesartan medoxomil dissolved. The mixture was then cooled to40° C., removed from the reactor, and filtered. The filtrate was thenreturned to reactor at maintained at 40° C. 375 mL (7.5 vol) water wasadded dropwise to the reactor over a period of 35 minutes, causingprecipitation. The reactor content was then cooled to 10° C. over aperiod of 3 hours. 125 mL (2.5 vol) of water was then added and thereactor content was cooled to 0° C. and stirred for 3 hours. Theprecipitated solids were filtered, washed with 100 mL (2 vol) of water,and dried at 50° C. under reduced pressure to give crystallineolmesartan medoxomil (91.5% yield). The OLM-acid content was 0.15%, asdetermined by HPLC.

Example 9 Impurity Profile Determination of Olmesartan Medoxomil

A 0.1% olmesartan medoxomil standard solution was prepared by diluting15 mg of olmesartan medoxomil standard in a 50 ml volumetric flask tovolume with diluent. This solution was diluted 1/50 and then 1/20 withdiluent.

An olmesartan medoxomil sample solution was prepared by diluting 15 mgof olmesartan medoxomil sample in a 50 ml volumetric flask to volumewith diluent.

The standard solutions were injected with a stop time of 20 minutes.

The sample solutions were injected continuing the chromatogram up to theend of gradient. HPLC Column & packing Discovery HS C18 50 * 4.6 mm, 3μC.N 269250-U Eluent A: 0.025 M NaClO₄ adjusted to pH = 2.5 with HClO₄Eluent B: Acetonitrile Time (min) Eluent A (%) Eluent B (%) Gradient ofEluent:  0 75 25 15 55 45 25 35 65 30 35 65 Stop time: 30 minEquilibration time: 5 min Flow: 1.5 ml/min Detector: 220 nm Injectionvolume: 10 μl Diluent 50% Eluent A:50% Eluent B Column temperature 25°C. Autosampler 5° C. temperature

The area of each impurity was determined using suitable integrator. Thedetection limit in the HPLC method of the OLM-acid is 0.01%.Calculations${\%\quad{Any}\quad{impurity}} = \frac{{Area}\quad{imp}\quad{smp} \times {{Conc}.{OLM}}\quad{std} \times {Potency}\quad{OLM}\quad{std}}{{{Conc}.{smp}} \times {Area}\quad{OLM}\quad{std}}$

The relative retention times for the chromatographic analysis (seeFIG. 1) are as follows: Substance RT RRT OLM-Acid 1.67 0.23 OLM 7.201.00 OLM-Methyl 8.66 1.20 OLM-Cl 9.05 1.26 OLM-Eliminate 9.41 1.31 TPC18.61 2.58 MTT 25.37 3.52

Having thus described the invention with reference to particularpreferred embodiments and illustrative examples, those in the art canappreciate modifications to the invention as described and illustratedthat do not depart from the spirit and scope of the invention asdisclosed in the specification. The examples are set forth to aid inunderstanding the invention but are not intended to, and should not beconstrued to, limit its scope in any way. The examples do not includedetailed descriptions of conventional methods.

1. Olmesartan medoxomil containing less than about 0.15% area by HPLCOLM-acid.
 2. The olmesartan medoxomil of claim 1, containing less thanabout 0.13% area by HPLC OLM-acid.
 3. The olmesartan medoxomil of claim2, containing less than about 0.12% area by HPLC OLM-acid.
 4. Apharmaceutical composition comprising the olmesartan medoxomil of claim1 and at least one pharmaceutically acceptable excipient.